The high prevalence of obesity in the US (17) is a major public health concern, as overweight and obese individuals are at increased risk for many chronic diseases (5, 7, 15, 18). Obesity stems from an imbalance between total caloric consumption and total energy expenditure (TEE), although the causes of this imbalance remain debated (29). Accurate and precise measurements of TEE therefore play a pivotal role in understanding and ultimately reversing this epidemic. TEE can be measured using direct (measurement of heat production) or indirect (measurement of respiratory gas exchange) calorimetry (4), but neither of these approaches are practical for measuring TEE in free living subjects. The gold standard for measuring TEE in free-living individuals is the doubly labeled water (DLW) method, which is based on the principle that the oxygen in body water is in complete isotopic equilibrium with the oxygen in dissolved respiratory carbon dioxide due to the action of carbonic anhydrase. The consequence of this exchange is that an isotopic label of oxygen introduced into body water is eliminated by the combined flux of body water and the exhaled carbon dioxide. Lifson and colleagues reasoned that, since hydrogen is found only in water and not in carbon dioxide, the elimination of a hydrogen isotope would be affected solely by the flux of body water (11). Thus the difference in the rates of isotope elimination of simultaneously administered oxygen and hydrogen labels is a measure of CO2 production.